11-oxygenated derivatives of 13-methyl-1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17-tetradecahydro-15h-cyclopenta [a] phenanthrene-3, 17-dione



11-0XYGENATED DERIVATIVES F 13-METHYL- 1,2,3,6,7,8,9,10,11,12,13,14,16,17 TETRADECAHY- DRO H CYCLOPENTA [a] PHENANTHRENE- 3,17-DIONE Leland J. Chitin, Morton Grove, 11]., assignor, by ntesne assignments, to G. D. Searle & Co., Skokie, III., a corporation of Delaware 1 No Drawing. Application June 11, 1953, Serial No. 361,069

1 Claim. Cl. 260-39745) The present invention relates to a new group of tetracyclic organic compounds and, more particularly, to 11- oxygenated derivatives of 13-methyl-1,2,3,6,7,8,9,10,11,- l2,13,14,16,17 tetradecahydro 15H cyclopenta[a]- phenanthrene-3,l7-dione which can be represented by the structural formula wherein X is an 0X0 orradical.

A convenient starting material for these compounds is 3 methoxy 13 methyl l,4,6,7,8,9,11,12,13,14,16,- 17 dodecahydro 15H cyclopenta[alphenanthren 17-one, described by Frank B. Colton in his copending application, Serial Number 286,611, filed May 7, 1952, issued as U. S. Patent No. 2,655,518. Treatment of this compound with dilute mineral acids yield l3-methyl-1,2,- 3,6,7,8,9,10,11,12,13,14,16,17 tetradecahydro 15H cyclopenta[alphenanthrene 3,17 dione. 11 hydroxylation is achieved by biochemical oxidation. 11ahydroxylation is produced by fungi and bacteria. The more valuable llfi-hydroxy compound is obtained by perfusion through a surviving mammalian adrenal gland.

1118 hydroxy 13 methyl 1,2,3,6,7,8,9,10,11,l2,- 13,14,16,17 tetradecahydro 15H r cyclopentalalphenanthrene-3,17-dione is a valuable hormonal agent. Unlike its IO-methyl derivative, it causes vaginal and uterine stimulation without interfering with adrenal corticoid balance or affecting the cardiovascular system. My invention also provides valuable intermediates in organic syn thesis. Thus oxidation of the 11-hydroxy group with chromium trioxide yields the 13-methyl-1,2,3,6,7,8,9,10,- l1,l2,13,14,16,17 tetradecahydro 15H cyclopenta' [a]phenanthrene-3,11,17-trione. Further valuable hormonal agents are obtained by the following series of reactions. Treatment of the 1l-hydroxy-l3-rnethyl-1,2,- 3,6,7,8,9,10,11,12,13,14,16,17 tetradecahydro 15H cyclopenta[alphenanthrene-3,l7-dione with ethyl orthoformate and p-toluenesulfonic acid yields 3-ethoxy-11- hydroxy 13 methyl l,2,7,8,9,10,11,12,13,14,16,17

7 2,772,298 Patented Nov. 27, 1956 dodecahydno 15H cyclopentalialphenanthren 17 one which, on hydrogenation with lithium aluminum hydride, yields the 3-ethoxy-13-methyl-1,2,7,8,9,l0,11,12,13,14,16,- 17 dodecahydro 15H cyclopenta[alphenanthrene 11,-17-diol of the structural formula CaHsO Cleavage of this ether with dilute mineral acid, e. g. with 5% hydrochloric acid in methanol, causes formation of 3 =oxo 1,2,3,6,,7,8, 9,10,11,12,13,14,16,17 tetradecahydro- 1 SH-cyclop enta a] plienanthrene-l 1 ,17-diol v OH:

the 1l}8-hydroxy isomer of which has valuable adrenocorticoid properties.

The compounds which constitute my invention and the methods for preparing them appear more fully from the examples below. However, the invention is not to be construed as limited by the details set forth in spirit or in scope. It will be obvious to those skilled in the art that many modifications in materials and methods can be practiced without departing trom the invention. In these examples temperatures are given in degrees centigrade (C.) and relative amounts of materials in parts by weight.

Example 1 A mixture of 192 parts of 3-methoxy-13-methyl-l,4,6,- 7,8,9,1l,12,13,14,16,17 dodecahydro 15H cyclopenta- [:alphenanthren-U-one and 1000 parts of 5% aqueous hydrochloric acid solution is heated for 8 minutes under nitrogen to 70 C. and then cooled. The oily layer is separated, triturated with water and washed successively with 5% sodium bicarbonate solution and water. The resulting 13 methyl 1,2,3,6,7,8,9,10,ll,12,13,14,16,17 tetradecahydro 15H cyclopenta[alphenanthrene 3,- 17-dione is recrystallized vfrom a mixture of ether and petroleum ether. Colorless plates are thus obtained Which melt at about 168170 C.

Example 2 In the course of 3 hours a stirred mixture of 1 part of 13 methyl 1,2,3,6,7,8,9,10,11,12,13,14,1 6,17 tetradecahydro 15H; "cyclopentaialphenanth-rene 3,17

dione, 5000 parts of citr'ated beef blood and 5000 parts of 0.85% aqueous sodium chloride solution is perfused twice through a surviving beef adrenal, cannulated through the vein and having a finely lacerated surface.

The per-fusate is frozen, thawed and extracted with isopropyl acetate. This extract is washed with water, dried by azeotropic distillation, concentrated to a residue of about 20 parts and then diluted with an equal volume of benzene. The mixture is applied to a chromatography column containing 95 parts of silica gel. The column is washed with 200 parts of a solution of ethyl acetate in benzene. "It is then eluted with 100 parts of a 25% and 50 parts of a 33% solution of ethyl acetate in benzene; concentration of these eluates yields unconverted starting material. The column is next eluted with 5.0. parts of a 33% and 50 parts of a 50% solution of ethyl-acetate in benzene. Then the column is eluted with 150 parts of a 50% solution of ethyl acetate in benzene and the eluate is concentrated under vacuum. Two

crystallizations of the residue from'ethyl acetate yield 11,8 hydroxy 13 methyl 1,2,3,6,7,8,9,10,11,12,13,- 14,16,17 tetradecahydro 15H cyclopentaialphenanthrene-3,-l7-dione, melting at about 194-196 C. The molecular rotation, as determined in a 1% chloroform solution, is [a] =+152. The ultraviolet absorption spectrum shows. a, maximum at about 242 millimicrons with a molecular extinction coefiicient of 17,400. The infrared spectrum shows maxima at 2.76, 5.78 and 6.03 microns. The compound has the structural formula Example 3 To. a. solution. of 8 parts, of 11 3-hydroxy 13rmethyl- 1,2,3,6,7,8,9,10,11,12,13,14,16,17 tetradecahydro 15H cyclopenta[a]phenanthrene-3,l7-dione in 400 parts of glacial acetic acid, a solution, of 13 parts of chromium trioxide in 400 parts of' water is added. The solution is maintained. at. 6-8. C. with occasional, agitation. After ad it on qr P rts of ha o o ssi li e excess oxidizing agent, the solution is poured into water and extracted with chloroform. This extract is Washed successively with water, 5% sodium hydroxide solution and water. l t-is then dried over anhydrous sodium sulfate and evaporated. Trituration of the residue with dry ether causes crystallization. Reoryst allized from methanol the l3-methyl-1,2,3,6,7,8,9,10,11,12,l3,l4,16,17-tetradecahydro 15H cyclopentalalphenanthrene 3,11,17 trione is obtained in th'ejform of heavy plates which melt at about 212-215 C. Infrared maxima are observed at 5.74, 5.84 and 6.02 microns. The compound has the structural formula References Cited in the file of this patent UNITED STATES PATENTS;

Murray et a1. July 8, 1952 Murray et al. Aug. 17, 1954 

